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Immunoassay for the in vitro quantitative determination of the MB isoenzyme of creatine kinase in human serum and plasma. Measurements of the MB isoenzyme of creatinine kinase are used as an aid in the diagnosis of myocardial infarction.
The electrochemiluminescence immunoassay "ECLIA" is intended for use on the indicated Elecsys and cobas e immunoassay analyzers.

The CK-MB STAT (one-step incubation) Assay is a sandwich immunoassay with streptavidin microparticles and electrochemiluminescence detection.
Results are determined using a calibration curve that is generated specifically on each instrument by a 2 point calibration and a master curve (5-point-calibration) provided with the reagent bar code.
The CK-MB STAT (one-step incubation) application is identical to the CK-MB STAT (two-step incubation) assay, the only difference being for the CK-MB STAT (one-step incubation) application, the sample, reagent 1, reagent 2 and microparticles are added at one time.

This document describes the acceptance criteria and study results for the Elecsys CK-MB STAT Immunoassay, a device used for the quantitative determination of the MB isoenzyme of creatine kinase in human serum and plasma, as an aid in diagnosing myocardial infarction.

This submission is a Special 510(k), indicating a modification to an existing device, the Elecsys CK-MB STAT (two-step incubation) Assay (K132571). The key difference in the modified device is the change to a one-step incubation protocol and its evaluation on the cobas e 601 Immunoassay Analyzer, compared to the predicate's two-step protocol on the cobas e 411.

1. Table of Acceptance Criteria and Reported Device Performance:

The document primarily focuses on demonstrating substantial equivalence to the predicate device by comparing various performance characteristics. The "Acceptance Criteria" for the modified device are generally considered to be equivalent to or better than the performance of the predicate device, or within acceptable clinical laboratory standards.

Study Proving Device Meets Acceptance Criteria:

The study conducted is a method comparison study to demonstrate that the modified Elecsys CK-MB STAT (one-step incubation) Assay on the cobas e 601 Immunoassay Analyzer performs substantially equivalently to the legally marketed predicate device, the Elecsys CK-MB STAT (two-step incubation) Assay on the cobas e 411.

Key Information about the Studies:

1. Sample Size used for the Test Set and Data Provenance:

   • Plasma Type Comparison: For each plasma type (Na Heparin, Li Heparin, K2-EDTA, K3-EDTA), "at least 30" or specific numbers rounded to 34 or 35 samples were used (e.g., 30 for Na Heparin, 35 for Li Heparin, 34 for K2-EDTA, 35 for K3-EDTA).
   • Linearity: 3 series of serum samples were used, with ranges from 0.13 to 563 ng/mL.
   • Precision: Not explicitly stated, but CLSI EP5-A2 guidelines typically involve multiple replicates (e.g., 2 runs per day for 20 days) for multiple samples (e.g., controls and patient samples at different concentrations). The performance values provided (e.g., %CV) are derived from such a study.
   • Interference (Common Pharmaceuticals and Special Drugs): Not explicitly stated, but "11 numerical values" were tested for general interferents, and "18 commonly used pharmaceuticals" and "33 special drugs" were tested.
   • Clinical/Reference Range: 523 female subjects and 568 male subjects ("apparently heart healthy") were used to establish the 99th percentile for the predicate device.
   • Method Comparison: A sample size of n = 115 was used, with CK-MB concentrations ranging from 1.47 ng/mL to 269 ng/mL.
   • Data Provenance: The document does not explicitly state the country of origin for the data or whether it was retrospective or prospective. Given that Rochester Diagnostics GmbH (Germany) is the submitter, it is likely that parts of the data originated from Europe, but this is not confirmed. The clinical study for reference ranges specifies "Subjects represented 'apparently heart healthy' population," which implies prospective selection, but the details are scarce.

2. Number of Experts Used to Establish Ground Truth for the Test Set and Qualifications:

   • For the analytical performance studies (precision, linearity, interference, analytical sensitivity, specificity), the "ground truth" is typically established by the reference methods/standards used for spiking, dilution, or comparison, rather than expert consensus on individual cases. For example, linearity samples are generated by diluting a high-concentration sample with a low-concentration matrix, and the expected values are the "ground truth."
   • For the clinical reference range, the "apparently heart healthy" population was selected based on "exclusion of subjects with known poor cardiac health or known peripheral vascular disease." This implies clinical assessment, but the number and qualifications of experts involved in this selection are not specified.
   • For the method comparison, the "ground truth" implicitly relies on the predicate device's established performance. No external experts are mentioned for establishing ground truth for the test set.

3. Adjudication Method for the Test Set:

   • Not applicable as this is an in-vitro diagnostic device for quantitative measurement, and the studies described are analytical performance evaluations and method comparisons against a predicate device. There is no mention of subjective interpretation of results requiring adjudication.

4. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study:

   • No, an MRMC comparative effectiveness study was not done. This type of study typically applies to imaging or diagnostic devices where human reader interpretation is a key component, often comparing AI-assisted reading to unassisted reading. The Elecsys CK-MB STAT Immunoassay is an in-vitro diagnostic test that provides a quantitative numerical result, not an image or complex data requiring human interpretation in the same way.

5. Standalone (Algorithm Only Without Human-in-the-Loop Performance) Study:

   • Yes, this is effectively a standalone performance study of the modified assay. The device itself (the immunoassay and the analyzer) is an automated system. The studies evaluate the analytical performance of this automated system directly (e.g., precision, linearity, analytical sensitivity, specificity, interference) and compare its output to the predicate device. There is no human-in-the-loop component in the direct measurement and reporting of CK-MB values by the device itself that would require a separate "human-in-the-loop" study.

6. Type of Ground Truth Used:

   • The ground truth for the performance studies is rooted in established laboratory standards, reference materials, and comparative methods.
     • Linearity: Gravimetric dilutions of known concentration samples.
     • Analytical Sensitivity: Statistical treatment of blank and low-concentration samples (CLSI EP17-A standard).
     • Analytical Specificity: Spiking samples with known concentrations of interfering substances (e.g., CK-MM, CK-BB, bilirubin, drugs) and measuring recovery.
     • Method Comparison: The established values measured by the predicate device (Elecsys CK-MB STAT two-step on cobas e 411) serve as the comparative standard.
     • Clinical Reference Range: Derived from measurements in a population of "apparently heart healthy" individuals, based on clinical exclusion criteria.

7. Sample Size for the Training Set:

   • This document describes a premarket notification (510(k)) for a modified immunoassay device, not a machine learning or AI algorithm in the traditional sense that requires a "training set." The development of such an assay involves extensive R&D, reagent formulation, and optimization which can be considered "training," but it doesn't involve a distinct "training set" of patient data in the same way an AI algorithm for image recognition would have. The performance studies detailed are for validation/testing of the developed assay.

8. How the Ground Truth for the Training Set was Established:

   • As noted above, the concept of a "training set" and associated "ground truth establishment" is not directly applicable in the context of this traditional immunoassay device's submission. The "training" for such a device is the iterative process of optimizing reagent concentrations, incubation times, antibody pairs, and detection methods during its analytical development, often guided by known chemical principles and calibrated against reference standards. The studies presented here are to validate the final optimized product.

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Immunoassay for the in vitro quantitative determination of the MB isoenzyme of creatine kinase in human serum and plasma. Measurements of the MB isoenzyme of creatinine kinase are used as an aid in the diagnosis of myocardial infarction. The electrochemiluminescence immunoassay "ECLIA" is intended for use on the indicated Elecsys and cobas e immunoassay analyzers.

The CK-MB STAT Assay and the CK-MB Assay are two-step sandwich immunoassays with streptavidin microparticles and electrochemiluminescence detection. Results are determined using a calibration curve that is generated specifically on each instrument by a 2-point calibration and a master curve (5-point-calibration) provided with the reagent bar code. The CK-MB STAT application is identical to the CK-MB assay, with the only difference being the length of incubation (9 minutes vs. 18 minutes).

This document describes the 510(k) Summary for the Elecsys CK-MB STAT and Elecsys CK-MB Immunoassays (4th Generation reagent). The purpose of the submission is to market a new reagent developed by Roche Diagnostics, claiming substantial equivalence to the previous 3rd Generation CK-MB STAT assay (K022654). The new reagent is intended for the in vitro quantitative determination of the MB isoenzyme of creatine kinase in human serum and plasma, used as an aid in diagnosing myocardial infarction on Elecsys and cobas e immunoassay analyzers.

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are generally implied by the performance characteristics of the predicate device and the goals for the new 4th Generation assay. The study demonstrated the performance of the new device (referred to as "4th Generation CK-MB STAT Assay (modified)" or "4th Generation CK-MB 18-Minute assay (modified)") against these implied benchmarks and established its own performance characteristics.

Here's a table summarizing the performance characteristics for both the predicate (3rd Generation Elecsys CK-MB STAT Assay) and the 4th Generation CK-MB STAT Assay (the primary focus of the comparison):

Study Proving Acceptance Criteria:

The studies presented in the 510(k) summary are direct comparisons demonstrating that the new 4th Generation Elecsys CK-MB STAT and Elecsys CK-MB Immunoassays meet performance criteria for substantial equivalence to the predicate device (Elecsys 3rd Generation CK-MB STAT Assay, K022654) and also illustrate the performance characteristics of the new assays themselves.

2. Sample Sizes Used for the Test Set and Data Provenance:

• Method Comparison (4th Gen STAT vs. Predicate): n = 165 serum samples.
• Method Comparison (4th Gen STAT vs. 4th Gen 18-Minute): n = 115 serum samples.
• Precision Testing (4th Gen STAT & 4th Gen 18-Minute): Performed using human serum samples and PreciControl Cardiac II over 21 days, according to CLSI EP5-A2. The number of samples for precision is not explicitly stated as 'n=' for unique patients but rather implied through the CLSI methodology.
• Analytical Sensitivity (LoB, LoD, LoQ): Determined in accordance with CLSI EP17-A requirements, involving n ≥ 60 measurements of analyte-free samples.
• Matrix Comparison (Plasma vs. Serum): 35 tubes collected per anticoagulant (Na-heparin, Li-heparin, K2-EDTA, K3-EDTA).
• Clinical Study/Reference Range Study: N = 760 women, 628 men for 3rd Gen (predicate). For 4th Gen, N=523 female, 568 male for all subjects, and N=120 female, 102 male for subjects with no self-reported risk factors. Subjects were "apparently heart healthy" with exclusion of known poor cardiac health.
• Data Provenance: The document does not explicitly state the country of origin for the patient samples. The studies were conducted internally by Roche Diagnostics. The nature of the studies (method comparisons, precision, analytical sensitivity, matrix comparisons) suggests these were primarily prospective laboratory studies designed to characterize the device's performance, rather than retrospective analysis of existing clinical data. The Clinical Study/Reference Range Study would typically involve prospective collection and analysis of de-identified healthy donor samples.

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Their Qualifications:

This submission concerns an in vitro diagnostic (IVD) immunoassay, not an imaging device or AI algorithm that requires human experts for ground truth establishment in the same way. The "ground truth" for this device is established through:

• Reference Methods: Comparison against a legally marketed predicate device (Elecsys 3rd Generation CK-MB STAT Assay) and comparison between the two new assays (STAT and 18-minute versions). The predicate device itself was cleared based on its own performance relative to established methods.
• Industry Standards: Adherence to CLSI (Clinical and Laboratory Standards Institute) guidelines (EP5-A2 for precision, EP17-A for analytical sensitivity, EP6-A for linearity). These guidelines define rigorous statistical and experimental approaches for evaluating assay performance.

Therefore, the "ground truth" is not established by a panel of human experts reviewing individual cases but by the analytical characteristics of the device when measured against well-defined reference standards and methods in laboratory settings, overseen by qualified laboratory scientists and statisticians.

4. Adjudication Method for the Test Set:

Not applicable in the context of an IVD immunoassay. Adjudication methods like 2+1 or 3+1 are typically used in clinical imaging studies where multiple human readers interpret results, and a consensus or tie-breaking mechanism is needed to establish ground truth for a dataset. For this immunoassay, performance is evaluated against quantitative measurements from other assays or statistical targets derived from CLSI guidelines.

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study:

No, an MRMC comparative effectiveness study was not done. This type of study is relevant for evaluating the impact of an AI system on human reader performance, particularly in diagnostic imaging. The Elecsys CK-MB STAT and Elecsys CK-MB Immunoassays are standalone laboratory diagnostic devices that provide quantitative measurements, not AI tools designed to assist human readers.

6. Standalone Performance Study (Algorithm Only):

Yes, the studies presented are essentially standalone performance studies of the reagent (the "algorithm" in a broad sense for an IVD). The various performance characteristics (measuring range, precision, analytical sensitivity, analytical specificity, hook effect, interference, and method comparisons) directly represent the performance of the immunoassay system (reagent + instrument) without human-in-the-loop assistance in interpreting the final quantitative result. The device provides a numerical value (ng/mL) directly.

7. Type of Ground Truth Used:

The ground truth for evaluating this immunoassay is primarily based on:

• Reference Measurement (Predicate Device): The performance of the new 4th Generation assay is compared against the established performance of the legally marketed 3rd Generation predicate device.
• Analytical Standards: Performance metrics like precision, analytical sensitivity (LoB, LoD, LoQ), and linearity are established using statistical methods defined by CLSI guidelines (e.g., EP5-A2, EP17-A, EP6-A). This involves using control materials and samples with known or precisely characterized analyte concentrations.
• Biological Samples: Human serum and plasma samples are used to assess performance characteristics, including method comparisons and matrix effects. The "true" value for these clinical samples is often assigned by the reference method or by a highly characterized comparative method.
• Traceability: The CK-MB STAT assay is traceable to the Abbott IMx CK-MB assay and linearized using human recombinant CK-MB from Seradyn, indicating an effort to link its measurements to recognized standards.

8. Sample Size for the Training Set:

The document does not specify a distinct "training set" sample size in the context of machine learning or AI. For IVD reagents, the development process involves extensive internal testing and optimization (which can be considered analogous to "training" and "validation" phases in AI development, but with biochemical and analytical methodology), but these details are typically not provided as specific "training set sizes" in 510(k) summaries. The data presented are performance validation data.

9. How the Ground Truth for the Training Set Was Established:

As above, the concept of a "training set" and its "ground truth" doesn't directly apply in the machine learning sense here. For reagent development and optimization, the "ground truth" during development would be established through a combination of:

• Known concentration standards and calibrators: Used to ensure the assay accurately measures CK-MB levels.
• Reference methods: Comparing experimental formulations against existing, well-characterized CK-MB assays.
• Clinical samples: Testing various formulations with a wide range of human serum and plasma samples, with consensus values likely derived from established methods or expert laboratories.
• Biochemical principles: Ensuring the immunoassay's capture and detection mechanisms accurately target the MB isoenzyme of creatine kinase.

The summary details the methods for determining analytical performance characteristics, indicating a rigorous scientific approach to developing and validating the device.

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